Dihydropyridines are used for the treatment of circulatory disorders and high blood pressure and are highly effective substances which, because of their side effects, must be administered to the patient specifically adapted in accordance with the clinical picture and individual need of the patient for the drug. From British Patent 11 73 862 it is known, for instance, that nifedipine, i.e. 4-(2-nitrophenyl)-2, 6-dimethyl-3, 5-dicarbomethoxy-1, 4-dihydropyridine, is to be administered orally in a dose of 2.5 mg per patient. For the treatment of angina pectoris, three doses per day, referred to patients of a weight of 70 kg, are to be given. This dose can be increased or reduced depending on the response of the patient. If larger doses are administered, they should be given in the form of several individual doses. Known adverse effects are nausea, dizziness, fatigue, skin reactions, tingling of the arms and legs, reduction of blood pressure below normal values, heart palpitation and increase in pulse rate. Nifedipine and its derivatives have biological half-lives which may differ under pathophysiological circumstances. Thus elimination half-lives of from 2 to 3 hours up to 4 to 11 hours are indicated for nifedipine. For other dihydropyridines such as nitrendipine, 6 to 15 hours are indicated and for nimodipine 1.5 to 2 hours and up to 22 hours in the case of chronic renal insufficiency with a creatinine clearance of less than 30 ml per minute.
These biopharmaceutical data indicate to tne skilled person that the producing of a steady state in the organism between the amount of active substance absorbed and the amount eliminated is problematical, for instance, in the case of nifedipine and its derivatives. In particular, an individual determination of the dose is needed for each patient in order to obtain therapeutically effective blood levels. Thereby it is necessary to dose in such a way that a reasonable ratio of effect to side effect is maintained.
This is imperfectly achieved, for instance, for nifedipine by the known initially liberating drug forms (chewable capsules, Federal Republic of Germany Patent 22 09 529). These initially acting forms for administration permit the active substance in the blood to increase rapidly to a high level up to peak concentrations which, as a rule, are not required for the treatment, then rapidly dropping again to sub-therapeutic concentrations (Dtsche Apoth. Ztg. 125 (1985), pages 1174-1176, FIG. 1). As compared with the minimum therapeutically active plasma concentration of 10-15 nanograms/ml (Selecta 10 (1983), page 860), that article mentions concentrations of up to 185 nanograms/ml. It follows from this that another dose must be administered again at the latest within three to four hours. Obviously with initially liberating forms of this kind, assured treatment can be obtained only with a large number of individual doses.
Drugs which must be administered several times a day for proper therapeutic treatment are frequently converted into formulations having a retarded, i.e. delayed, characteristic of liberation. Retardation is meaningful if the elimination halflife of the active substance is sufficiently short and/or the regularity of ingestion (patient compliance) is to be improved by this measure. The purpose of retardation is to form, after repeated administration a uniform, therapeutically active blood level with the lightest possible variation between C.sub.max and C.sub.min (i.e. between maximum and minimum blood level concentrations).
Thus different retard forms and methods for the manufacture thereof are known also for nifedipine and its derivatives.
British Patent 20 53 681 describes retard formulations for the dihydropyridines nicardipine and nifedipine in which the substance in question is present in amorphous form together with polyethylene oxide and other adjuvants.
In Federal Republic of Germany OS 30 24 858, the German counterpart of British Patent 20 53 681, additional results of a bioavailability as compared with the control, nevertheless clearly show that the blood levels drop after at most 6 hours.
British Patent 21 59 407 describes a solid nifedipine formulation using casein and inorganic adjuvants. It is evident from the bioavailability testing that uniform blood levels are obtained for a period of 4-6 hours, followed by a rapid decline (FIG. 7).
European Patent A-00 47 899 teaches the production of nifedipine-containing solid drug formulations in which the active substance is present with a well-defined specific surface. Use is made of the self-retardation of practically water-insoluble nifedipine crystals (slow dissolving of the crystals).
The indicated plasma concentrations show for Example 1 of EP-A-00 47 899, a rapid surge after the first hour and a plateau-like course for the second to eighth hours, followed by a rapid decline to a lower level. The curve for Example 2 shows a plateau from the first to the sixth hours, followed by a decline.
In addition, the state of the art is formed by the preparations available on the market and their dosage recommendations. All known nifedipine retard preparations are taken, according to the information given by the manufacturer, one tablet two times a day up to four times a day with an interval of 4 to 12 hours between tablets. The nifedipine derivative nimodipine is administered orally as Nimotop.RTM. in six hour intervals four times a day with 2 tablets of 30 mg each (Red List 1986, Consecutive No. 26084).
For commercial nifedipine-containing retard forms it is shown, on the basis of a bioavailability study, that despite retardation the active substance rapidly increases to peak concentrations (which are far above the therapeuticaIly required concentrations) and, at the latest within 10 hours, the concentration drops below the minimum therapeutic level of activity (Arzneim.-Forsch./Drug Res. 35 (II), No. 12, 1983, pages 1840-1842).
It follows from these data and measurement results that, while it is possible to retard nifedipine and its related substance in order to obtain blood level concentrations which are retained for a long time, nevertheless these attempts have remained imperfect, as shown in practical use.